Antiviral therapies are urgently needed to treat infections with flaviviruses such as Zika (ZIKV) and dengue (DENV) virus. Repurposing FDA-approved compounds could provide the fastest route to alleviate the burden of flaviviral diseases. In this study, three fluoroquinolones, enoxacin, difloxacin and ciprofloxacin, curtailed replication of flaviviruses ZIKV, DENV, Langat (LGTV) and Modoc (MODV) in HEK-293 cells at low micromolar concentrations. Time-of-addition assays revealed that enoxacin suppressed ZIKV replication when added at 6 hours post-infection, suggesting inhibition of an intermediate step in the virus life cycle, whereas ciprofloxacin and difloxacin had a wider window of efficacy of 2, 6, and 8 hours post-infection for difloxacin and 2 to 8 hours post-infection for ciprofloxacin. The efficacy of enoxacin to suppress ZIKV replication in 5-week-old A129 mice was evaluated in two experiments. First, mice were infected with 1x105 plaque-forming units (pfu) ZIKV FSS13025 (n=20) or PBS (n=11) on day 0 and subsets were treated with enoxacin at 10mg/kg or 15mg/kg or diluent orally twice daily on days 1-5. Treated and control mice did not differ in weight change or virus titer in serum or brain. Mice treated with enoxacin showed a significant, 5-fold decrease in ZIKV titer in testes relative to controls. Second, mice were infected with 1x102 pfu ZIKV (n=13) or PBS (n=13) on day 0 and subsets were treated with 15mg/kg oral enoxacin or diluent twice daily on days 0 (pre-treatment) and 1-5. Mice treated with enoxacin showed a significant, 2.5-fold decrease in ZIKV titer in testes relative to controls, while weight and viral load in the serum, brain, and liver did not differ between treated and control mice. Enoxacin efficacy in cultured murine Sertoli cells was not enhanced compared to efficacy in HEK-293 cells. ZIKV can be sexually transmitted, so reduction of titer in the testes by enoxacin should be further investigated.

中文翻译：

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具有新技巧的旧药：氟喹诺酮类药物抑制黄病毒复制的功效

迫切需要抗病毒疗法来治疗黄病毒（例如寨卡病毒（ZIKV）和登革热病毒（DENV））的感染。重新利用FDA批准的化合物可以提供减轻黄病毒疾病负担的最快途径。在这项研究中，三种氟喹诺酮类药物（依诺沙星，地氟沙星和环丙沙星）在低微摩尔浓度下限制了黄病毒ZIKV，DENV，Langat（LGTV）和Modoc（MODV）在HEK-293细胞中的复制。添加时间分析显示，在感染后6小时添加时，依诺沙星抑制了ZIKV复制，表明抑制了病毒生命周期的中间步骤，而环丙沙星和地氟沙星的疗效范围更广，分别为2、6和8地氟沙星在感染后2小时内，环丙沙星在感染后2至8小时内。在两个实验中评估了依诺沙星抑制5周龄A129小鼠中ZIKV复制的功效。首先，在第0天用1x105斑块形成单位（pfu）ZIKV FSS13025（n = 20）或PBS（n = 11）感染小鼠，然后每天两次以10mg / kg或15mg / kg的依诺沙星或稀释剂口服治疗子集在1-5天。治疗和对照小鼠的体重或血清或脑中病毒滴度无差异。依诺沙星处理的小鼠的睾丸ZIKV滴度相对于对照组显着降低了5倍。其次，在第0天用1x102 pfu ZIKV（n = 13）或PBS（n = 13）感染小鼠，并在第0天（预处理）和第1-5天每天两次用15mg / kg口服依诺沙星或稀释剂治疗小鼠。与依诺沙星相比，依诺沙星治疗的小鼠睾丸ZIKV滴度明显降低了2.5倍，而治疗小鼠和对照组小鼠的血清，大脑和肝脏的重量和病毒载量没有差异。与在HEK-293细胞中的功效相比，依诺沙星在培养的鼠支持细胞中的功效没有增强。ZIKV可以通过性传播，因此应进一步研究依诺沙星降低睾丸滴度的方法。